State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Sci Adv. 2021 Jan 20;7(4). doi: 10.1126/sciadv.abe5689. Print 2021 Jan.
Polycomb group (PcG) proteins form multiprotein complexes that affect stem cell identity and fate decisions by still largely unexplored mechanisms. Here, by performing a CRISPR-based loss-of-function screen in embryonic stem cells (ESCs), we identify PcG gene involved in the repression of endodermal transcription factor We report that deletion of results in peri-implantation embryonic lethality in mice. We further demonstrate that -null ESCs exhibit impaired self-renewal and spontaneous differentiation to primitive endoderm (PE). Our data support a model in which Mga might serve as a scaffold for PRC1.6 assembly and guide this multimeric complex to specific genomic targets including genes that encode endodermal factors Gata4, Gata6, and Sox17. Our findings uncover an unexpected function of Mga in ESCs, where it functions as a gatekeeper to prevent ESCs from entering into the PE lineage by directly repressing expression of a set of endoderm differentiation master genes.
多梳抑制复合物（PcG）蛋白形成多蛋白复合物，通过仍在很大程度上尚未探索的机制影响干细胞的身份和命运决定。在这里，我们通过在胚胎干细胞（ESCs）中进行基于 CRISPR 的功能丧失筛选，鉴定了参与内胚层转录因子的 PcG 基因的抑制。我们报告说，缺失导致小鼠在植入前胚胎致死。我们进一步证明-缺失的 ESCs 表现出自我更新受损和自发分化为原始内胚层（PE）。我们的数据支持这样一种模型，即 Mga 可能作为 PRC1.6 组装的支架，并将这个多聚体复合物引导到特定的基因组靶标，包括编码内胚层因子 Gata4、Gata6 和 Sox17 的基因。我们的发现揭示了 Mga 在 ESCs 中的一个意外功能，它作为一个守门员，通过直接抑制一组内胚层分化主基因的表达，防止 ESCs 进入 PE 谱系。
